Fast dissolving pharmaceutical composition

ABSTRACT

The subject invention is directed to a pharmaceutical composition comprising an open matrix network carrying a pharmaceutically active ingredient, wherein the open matrix network comprises both the polysaccharides levan and inulin.

FIELD OF THE INVENTION

The subject invention relates to fast dissolving pharmaceuticalcompositions, to methods of making them and to their use in thetreatment and prophylaxis of diseases in mammals, particularly humans.

BACKGROUND OF THE INVENTION

Fast dissolving pharmaceutical dosage forms which are designed torelease an active ingredient in the oral cavity are well known and canbe used to deliver a wide range of drugs (Critical Reviews inTherapeutic Drug Carrier Systems, 21(6): 433-475 (2004); Seager H.(1998), J. Phar. Pharmacol 50:375-382; Bandari et al. (January 2008),Asian Journal of Pharmaceutics 2-11).

In a fast dissolving dosage form, a drug may physically be trapped in amatrix composed of e.g. mannitol and fish gelatin (EP 1501534;EP1165053), modified starch (U.S. Pat. No. 6,509,040), pullulan incombination with an amino acid (EP1803446), or maltodextrin incombination with sorbitol (US2004/0228919). The solution, suspension ordispersion of the drug and the carrier material may be filled intoblister cavities, frozen and thereafter lyophilized. However, dosageforms produced in this manner are mostly fragile and brittle, havelimited physical strength, and cannot withstand any pressure. Inaddition, dosage units so produced are difficult to pack and unpack.

The subject invention provides an improved fast-dispersing dosage form.

SUMMARY OF THE INVENTION

The subject invention provides new fast dissolving oral pharmaceuticalcompositions typically in a unit dosage form, typically orallyophilisates (also named orally disintegrating tablets). Fastdissolving dosage forms of the invention have relatively high tensilestrength (i.e. force required to break a tablet in a three-point bendingtest) on the one hand and a fast disintegration/dissolution time on theother hand. This relatively high tensile strength permits, amongstothers, to easily remove the composition from its container, typically ablister pack, without disintegration. The unit dosage form of theinvention can typically be handled in a manner similar to that of aconventional compressed tablet, with disintegration occurring only uponcontact with an aqueous liquid or with saliva within the mouth.

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising an open matrix network carrying apharmaceutically active ingredient, wherein the open matrix network iscomprised of both levan and inulin.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a matrix carrying a pharmaceutically activeingredient, the matrix rapidly disintegrating upon contact with anaqueous solution or with saliva, said matrix comprising levan andinulin.

The pharmaceutical composition of the invention is unique in that it hasa relatively high tensile strength, on the one hand, and a rapiddissolution in an aqueous medium or in saliva, on the other hand.

The relatively high tensile strength permits the handling of thecomposition in a manner similar to that of a regular compressed tabletincluding, in particular, removal from a package in which they are held,e.g. a blister pack, without risk of damaging the dosage form betweenthe fingers. Notwithstanding this tensile strength, the composition ofthe invention disintegrates rapidly when contacted with an aqueousmedium or with saliva, in particular the composition rapidlydisintegrates when taken orally. The disintegration in an aqueous mediumor in the oral cavity upon consumption (where it disintegrates uponcontact with saliva) is typically within less than 30 seconds, and moretypically within less than 10 seconds, at times less than 9, 8, 7, 6, 5,4, 3, 2 or even 1 second.

Accordingly, the invention further provides a pharmaceutical compositioncomprising a pharmaceutically active ingredient, having a tensilestrength so as to allow consumer handling of the composition (typicallyin a unit dosage form) in a manner similar to that of a compressedtablet, the pharmaceutical composition of the invention typically havinga tensile strength ranging between about 0.05 to 1.6 N/mm² and a rapiddissolution rate such that at least 80% of the composition isdisintegrated in an aqueous medium or in saliva in less that 30 seconds,at times less than 10 seconds and even less than 9, 8, 7, 6, 5, 4, 3, 2,or 1 second.

The pharmaceutical composition of the invention may be obtained bysubliming a solvent (e.g. water), for example in a freeze dryingprocess, from a liquid preparation that comprises the active ingredientand the matrix forming agent(s) in solution. According to oneembodiment, unit dosage quantities of the liquid preparation areintroduced into depressions and sublimation is then carried out therebyobtaining (after sublimation) a pharmaceutical composition in a unitdosage form. The depressions may be those of an open blister pack andfollowing the sublimation step, and thereby the formation of the solidunit dosage form of the composition in the depression, a sealing film orfoil is placed over the depressions to form a sealed blister pack.

The invention further provides a process for preparing a pharmaceuticalcomposition that comprises subliming a solvent from a liquid preparationcomprising a pharmaceutically active ingredient and levan and inulin inthe solvent.

The invention also provides a process for the preparation of apharmaceutical composition comprising (a) preparing a solutioncomprising levan and inulin and an active ingredient in a solvent; (b)freezing said solution; (c) subliming the solvent from the frozensolution, wherein the pharmaceutical composition so obtained is infast-dispersing dosage form which disintegrates within less than 30seconds upon contact with an aqueous solution or with saliva.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention provides a fast-dissolving, typicallyorodispersible, pharmaceutical composition, usually prepared andprovided in unit dosage form, typically an oral lyophilisate, comprisingan active ingredient and one or more excipients. At least two of theexcipients, normally the main matrix forming agents are thepolysaccharides levan and inulin.

The following are some of the terms used above and below in this patentspecification and claims:

The terms “active ingredient” or “pharmaceutically active ingredient”will be used interchangeably herein.

The term “pharmaceutical composition” and “composition” areinterchangeably used herein to refer to a pharmaceutical composition ofthe invention.

The term “unit dosage form” or “dosage form” will be used herein torefer to said composition which is formulated with an amount of anactive pharmaceutical ingredient (API) in a dose for administration as asingle dose to a target individual. The unit dosage form may be adapted,depending on the nature of the active ingredient, the indication, thedisease stage and various other factors known per se for once, twice,thrice or any other number of daily administrations.

The term “carrying” should be understood to encompass any form ofinteraction between an active ingredient and the matrix that allows thematrix to hold and/or contain an amount of active ingredient and releaseit to the aqueous medium or to saliva upon disintegration of the matrix.

The term “matrix” should be understood to denote a solid carrier mediumfor an active ingredient. The matrix comprises at least two excipients.The excipients that form the matrix may be referred to herein, at times,as “matrix forming agents” and each of said agents as “matrix formingagent”.

The term “an open matrix network” should be understood to encompass amatrix of water-soluble or water-dispersible carrier material(matrix-forming agent(s)) having interstices dispersed throughout. Thematrix rapidly disintegrates upon contact with an aqueous solution orwith saliva.

In one embodiment, levan and inulin are the matrix forming agents in thecomposition. In another embodiment, one or more secondary matrix formingagents may be present in the composition.

Non-limiting examples of sugars, sugar alcohols, monosaccharides,disaccharides, trisaccharides, polysaccharides, proteins, amino acids,gums and the like, which are useful as secondary matrix forming agents,include without limitation, mannitol, trehalose, raffinose, inositol,pullulan, sucrose, lactose, dextrose, erythritol, xylitol, lactitol,maltitol, isomalt, alanine, arginine, threonine, glycine, cysteine,serine, histidine, valine, proline, lysine, asparagine, glutamine,ribose, glucose, galactose, fructose, maltose, maltotriose, guargum,xanthan gum, tragacanth gum, veegum and so forth.

Generally, the balance of the formulation can be matrix. Thus thepercentage of the levan and inulin matrix can approach 100%. The amountof the secondary matrix forming agent useful in accordance with thepresent invention may range from about 0 to about 90%.

In one embodiment of the invention, levan is the main matrix formingagent in the composition. In another embodiment, inulin is the mainmatrix forming agent in the composition. In yet another embodiment, thecomposition further comprises mannitol or raffinose or trehalose orcombinations thereof as secondary matrix forming agent.

In one embodiment, levan and inulin are the matrix forming agents,comprising 10-99.99% out of the entire weight of the composition. Inanother embodiment, levan and inulin comprise 30-85% out of the entireweight of the composition. In yet another embodiment, levan and inulincomprise 40-70% out of the entire weight of the composition. In yetanother embodiment, levan and inulin comprise 50-65% out of the entireweight of the composition.

In other embodiments, mannitol or trehalose or raffinose or combinationsthereof are used as secondary matrix forming agents, comprising 0-89.99%out of the entire weight of the composition. In one embodiment, thesesecondary matrix forming agents comprise 15-50% out of the entire weightof the composition. In another embodiment, these secondary matrixforming agents comprise 25-50% out of the entire weight of thecomposition.

Thus, a composition of the invention can be one comprising levan andinulin as the main matrix-forming agents and mannitol or trehalose orraffinose (or combinations thereof) as secondary matrix-forming agent,with levan and inulin constituting 10-99.99% (all % of ingredient arew/w, meaning weight of mentioned ingredient out of the weight of allconstituents of the composition combined), and the secondary matrixforming agent constituting 0-89.99%, typically 25-50%. The content ofthe active ingredient may typically (but not exclusively) be up to 90%of the entire composition, typically in the range of 0.01-70% dependingon the nature of the active ingredient. In one embodiment, the activeingredient comprises 0.01-1% out of the entire weight of thecomposition. In another embodiment, the active ingredient comprises0.5-2% out of the entire weight of the composition. In yet anotherembodiment, the active ingredient comprises 5-30% out of the entireweight of the composition. In other embodiments, the active ingredientcomprises 20-40% out of the entire weight of the composition. In yetother embodiments, the active ingredient comprises 60-90% out of theentire weight of the composition.

In one embodiment, the composition of the invention does not containfish gelatin. In another embodiment, the composition of the inventiondoes not contain a modified starch. In another embodiment, thecomposition of the invention does not contain pullulan in combinationwith an amino acid. In another embodiment, the composition of theinvention does not contain maltodextrin in combination with sorbitol.

“Disintegration Time” and “Dissolution Time” are used interchangeablyherein and should be understood to mean the time needed to dissolve ordisintegrate a composition of the invention in an aqueous solution orwith saliva within the oral cavity.

“Oral dissolving Time” as used herein should be understood to mean thetime needed to dissolve a composition of the invention in the oralcavity.

“Rapid/Fast disintegration/dissolution” as used herein should beunderstood to encompass disintegration of at least 80% of a compositionof the invention, typically 90% and more typically 100% of thecomposition in an aqueous medium or in saliva (in the oral cavity)within 30 seconds, typically within 10 seconds and at times even within9, 8, 7, 6, 5, 4, 3, 2 or 1 second.

Examples of an aqueous medium as used herein are water or a buffer (e.g.potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodiumhydrogen phosphate) or artificial saliva as described by Morjaria et. al(May 2004), Dissolution Technologies 12-15.

Saliva as used herein refers to the saliva in the oral cavity of amammal, in particular a human.

“Tensile strength” as used herein should be understood to be the forcerequired to break a tablet, which is measured by the three-point bendingtest, wherein the tablet is subjected to a bending stress (Mohd etal.(2002), Drug Development and Industrial Pharmacy 28(7):809-813).

In one embodiment, a pharmaceutical composition of the invention has atensile strength in the range of about 0.05-1.6 N/mm². In anotherembodiment, a pharmaceutical composition of the invention has a tensilestrength in the range of about 0.05-1.4 N/mm². In yet anotherembodiment, a pharmaceutical composition of the invention has a tensilestrength in the range of about 0.1-0.3 N/mm².

It is envisaged that a pharmaceutical composition of the invention has arapid disintegration/dissolution rate such that at least 80% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds. In one embodiment, apharmaceutical composition of the invention has a rapiddisintegration/dissolution rate such that at least 90% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In one embodiment, a pharmaceutical composition of the invention has atensile strength in the range of about 0.05-1.6 N/mm² and a rapiddisintegration/dissolution rate such that at least 80% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a pharmaceutically active ingredient, having atensile strength ranging between about 0.05 to 1.4 N/mm² and a rapiddisintegration/dissolution rate such that at least 80% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a pharmaceutically active ingredient, having atensile strength ranging between about 0.1 to 0.3 N/mm² and a rapiddisintegration/dissolution rate such that at least 80% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In one embodiment, a pharmaceutical composition of the invention has atensile strength in the range of about 0.05-1.6 N/mm² and a rapiddisintegration/dissolution rate such that at least 90% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a pharmaceutically active ingredient, having atensile strength ranging between about 0.05 to 1.4 N/mm² and a rapiddisintegration/dissolution rate such that at least 90% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a pharmaceutically active ingredient, having atensile strength ranging between about 0.1 to 0.3 N/mm² and a rapiddisintegration/dissolution rate such that at least 90% of thecomposition is dissolved in an aqueous medium or in saliva within 30seconds, typically within 10 seconds.

The open matrix network enables a liquid to enter the dosage formthrough the interstices and permeate through its interior. Permeation byaqueous media (such as saliva, water, etc.) exposes the carrier materialof both the interior and exterior of the dosage form to the action ofthe aqueous media or saliva whereby the network of carrier material israpidly disintegrated/dissolved.

The open matrix structure is of a porous nature and enhancesdisintegration of the dosage form as compared with ordinary solid shapedpharmaceutical dosage forms such as (granulated and compressed) tablets,pills, capsules, suppositories and pessaries. Rapid disintegrationresults in rapid release of the active ingredient carried by the matrix.

In the subject invention, the carrier material of the open matrixnetwork is levan or a derivative thereof in combination with inulin or aderivative thereof.

Levan (also named leaven, levulosan, polyfructosan, polyfructose andpolylevulan) is a polymer of fructose C₆H₁₂O₆. Levan is a polysaccharidewith β-(2→6) linkages between the fructose rings where the numbersdescribe the carbon atoms in the fructose ring which are linked and theβ describes the stereochemical relationship. Levans have also beendescribed as fructans in which the predominant glycosidic linkagebetween the D-fructofuranoside monomeric units is β-(2→6). The levansare generally made by microorganisms and do not occur as high molecularweight compounds in plants. Some low molecular weight levans having amolecular weight of less than 100,000 Daltons can occur in grasses.

“Levan” as used herein should be understood to encompass levan derivedfrom any one or more sources such as but not limited to A. indicus, A.versicolor, Acetobacter suboxydans, Achromobacter spp., Actinomycenessp., Actinomyces viscosus, Aerobacter aerogenes, Aerobacter levanicum,Aspergillus sydowi, Azotobacter chroococcum, Bacillus polymyxa, Bacilluslicheniformis, Bacillus macerans, Bacillus megatherium, Bacillusmesentericus, Bacillus subtilis, Bacillus vulgatus, Corynbacteriumlaevaniformans, Erwinia herbicola, Gluconobacter oxydans, Leuconostocmesenteroides, Odontomyces viscosus, Phytobacterium vitrosum, Phytomonaspruni, Psuedomonas Fluorescens, Pseudomonas Syringae, Pseudomonasprunicola, Rothis dentocariosa, Serratia kiliensis, Steptococcus bovis,Steptococcus mutans, Steptococcus salivarius, Xanthomonas campestris,Xanthomonas pruni, Zymomonas mobilis and so forth. In a specificembodiment, the levan is obtained from Zymomonas and Bacillus species.In a more specific embodiment, the levan is obtained from Zymomonasmobilis.

It should be understood that also derivatives of levan (e.g. asdescribed in WO98/03184) can be used in place of levan.

Inulin is a polymer of fructose C₆H₁₂O₆ typically having a terminalglucose. Inulin is a polysaccharide with β-(2→1) linkages between thefructose rings where the numbers describe the carbon atoms in thefructose ring which are linked and the β describes the stereochemicalrelationship. The inulins are produced by many type of plants.

Inulin as used herein should be understood to encompass inulin derivedfrom any one or more sources such as but not limited to plants thatcontain high concentrations of inulin which include, but are not limitedto Elecampane (Inula helenium); Dandelion (Taraxacum officinale); WildYam (Dioscorea spp.); Jerusalem artichokes (Helianthus tuberosus);Chicory (Cichorium intybus); Jicama (Pachyrhizus erosus); Burdock(Arctium lappa); Onion (Allium cepa); Garlic (Allium sativum); Agave(Agave spp.); Yacón (Smallanthus sonchifolius spp.); and Camas (Camassiaspp.). In a specific embodiment, the Inulin is obtained from Chicory(Cichorium intybus).

The pharmaceutically active ingredient may encompass any pharmaceuticalingredient such as a drug, a compound, a peptide, a polypeptide, anucleotide, and so forth.

Non-limiting examples of drugs which can be carried by the open matrixnetwork of the subject invention are analgesics, alpha blockers,anti-allergy, anti-asthma, (allergic rhinitis, chronic uticaria),anti-inflammatory, antacids, anthelmintics, anti-arrhythmic agents,anti-arthritis, anti-bacterial, anti-anxiety, anti-coagulants,anti-depressants, anti-diabetics, anti-diarrheals, anti-diuretics,anti-epileptics, anti-fungal, anti-gout, anti-hypertensive,anti-incontinence, anti-insomnia, anti-malarials, anti-migraine,anti-muscarinic, anti-neoplastic and immunosuppressants, anti-protozoal,anti-rheumatics, anti-rhinitis, anti-spasmatic. anti-thyroid,antivirals, anxiolytics, sedatives, hypnotics and neuroleptics,beta-blockers, anti-benign hyperplasia (BHP), cardiac inotropic,corticosteroids, cough suppressants, cytotoxics, decongestants, diabeticgastric stasis, diuretics, enzymes, anti-parkinsonian,gastro-intestinal, histamine receptor antagonists, infertility,endometriosis, hormone replacement therapy, lipid regulating agents,local anesthetics, neuromuscular agents, nitrates and anti-anginalagents, menstrual disorders, motion sickness, anti-pain, anti-nausea,movement disorders, nutritional agents, opioid analgesics, oralvaccines, proteins, peptides and recombinant drugs, prevention ofchemotherapy induced and post operative nausea and vomiting proton pumpinhibitors, schizoprenia, sex hormones and contraceptives, seizure/panicdisorder, sexual dysfunction (male and female), spermicides, stimulantsvoiding dysfunctions, veterinary medicines and so forth.

Specific non-limiting examples of these drugs are:

-   -   Alfa blockers: Tamsulosine    -   Analgesics and anti-inflammatory agents: aspirin, aloxiprin,        auranofin, azapropazone, benorylate, diflunisal, etodolac,        fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen,        indomethacin, ketoprofen, meclofenamic acid, mefenamic acid,        nabumetone, naproxen, oxaprozin, oxyphenbutazone,        phenylbutazone, piroxicam, sulindac, paracetamol.    -   Antacids: aluminum hydroxide, magnesium carbonate, magnesium        trisilicate, hydrotalcite, dimethicone.    -   Antihelmintics: albendazole, bephenium hydroxynaphthoate,        cambendazole, dichlorophen, ivermectin, mebendazole,        oxamniquine, oxfendazole, oxantel embonate, praziquantel,        pyrantel embonate, thiabendazole.    -   Anti-allergic: des loratidine, loratidine, Montelukast,        Montelukast sodium, Cetirizin, Fexofenadin, Ebastine.    -   Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainide        acetate, quinidine sulphate.    -   Anti-bacterial agents: benethamine penicillin, cinoxacin,        ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin,        demeclocycline, doxycycline, erythromycin, ethionamide,        imipenem, nalidixic acid, nitrofurantoin, rifampicin,        spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,        sulphacetamide, sulphadiazine, sulphafurazole,        sulphamethoxazole, sulphapyridine, tetracycline, trimethoprim.    -   Anti-coagulants: dicoumarol, dipyridamole, nicoumalone,        phenindione.    -   Anti-depressants: amoxapine, ciclazindol, maprotiline HCl,        mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine        maleate.    -   Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide,        gliclazide, glipizide, tolazamide, tolbutamide.    -   Anti-diarrheals: atropine sulphate, codeine phosphate,        co-phenotrope, difenoxin, loperamide hydrochloride,        suphasolazine, mesalazine, olsalazine, corticosteroids,        prednisolone.    -   Anti-diuretics: desmopressin, desmopressin acetate.    -   Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin,        methoin, methsuximide, methylphenobarbitone, oxcarbazepine,        paramethadione, phenacemide, phenobarbitone, phenytoin,        phensuximide, primidone, sulthiame, valproic acid.    -   Anti-fungal agents: amphotericin, butoconazole nitrate,        clotrimazole, econazole nitrate, fluconazole, flucytosine,        griseofulvin, itraconazole, ketoconazole, miconazole, natamycin,        nystatin, sulconazole nitrate, terbinafine HCl, terconazole,        tioconazole, undecenoic acid.    -   Anti-gout agents: allopurinol, probenecid, sulphinpyrazone.    -   Anti-hypertensive agents: amlopidine, benidipine, darodipine,        dilitazem HCl, diazoxide, felodipine, guanabenz acetate,        indoramin, isradipine, minoxidil, nicardipine HCl, nifedipine,        nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine,        terazosin HCl.    -   Anti-insomnia: Zolpidem    -   Anti-malaria: amodiaquine, chloroquine, chloroproguanil HCl,        halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine,        quinine sulphate.    -   Anti-migraine agents: rizatriptan, dihydroergotamine mesylate,        ergotamine tartrate, methysergide maleate, pizotifen maleate,        sumatriptan succinate, caffeine.    -   Anti-muscarinic agents: oxybutinin, tolterodin, atropine,        benzhexol HCl, biperiden, ethopropazine HCl, hyoscine butyl        bromide, hyoscyamine, mepenzolate bromide, orphenadrine,        oxyphencylcimine HCl, tropicamide.    -   Anti-neoplastic agents and Immunosuppressants:        aminoglutethimide, amsacrine, azathioprene, busulphan,        chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide,        lomustine, melphalan, mercaptopurine, methotrexate, mitomycin,        mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate,        testolactone.    -   Anti-protozoal agents: benznidazole, clioquinol, decoquinate,        diiodohydroxyquinoline, diloxanide furcate, dinitolmide,        furzolidone, metronidazole, nimorazole, nitrofurazone,        ornidazole, tinidazole.    -   Anti-rheumatics: ibuprofen, aceclofenac, acemetacin,        azapropazone, diclofenac sodium, diflunisal, etodolac,        ketoprofen, indomethacin, mefenamic acid, naproxen, piroxicam,        aspirin, benorylate, auranofin, penicillamine.    -   Anti-rhinitis, anti-uticaria: Cetirizin, fexofenadin, ebastine,        loratidin, montelukast    -   Anti-spasmatic: phloroglucinol anhydre    -   Anti-thyroid agents: carbimazole, propylthiouracil.    -   Antivirals: acyclovir, amantadine hydrochloride, famciclovir,        zidovadine, didanosine, zalcitabine, foscarnet sodium.    -   Anxiolytic, sedatives, hypnotics and neuroleptics: alprazolam,        amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol,        brotizolam, butobarbitone, carbromal, chlordiazepoxide,        Chlorpheniramine, chlormethiazole, chlorpromazine, clobazam,        clonazepan, clotiazepam, clozapine, diazepam, droperidol,        ethinamate, flunanisone, flunitrazepam, fluopromazine,        flupenthixol decanoate, fluphenazine decanoate, flurazepam,        haloperidol, lorazepam, lormetazepam, medazepam, meprobamate,        methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone,        perphenazine phenylephrine, pimozide, prochlorperazine,        pseudoephedrine HCL, sulpride, temazepam, thioridazine,        triazolam, zopiclone.    -   β-Blockers: acebutolol, alprenolol, atenolol, labetalol,        metoprolol, nadolol, oxprenolol, pindolol, propanolol.    -   Cardiac inotropic agents: amrinone, digitoxin, digoxin,        enoximone, lanatoside C, medigoxin.    -   Corticosteroids: beclomethasone, betamethasone, budesonide,        cortisone acetate, desoxymethasone, dexamethasone,        fludrocortisone acetate, flunisolide, flucortolone, fluticasone        propionate, hydrocortisone, methylprednisolone, prednisolone,        prednisone, triamcinolone.    -   Cough suppressants: codeine phosphate dexomethorphan,        guaifenesin, pholcodine, diamorphine, methadone.    -   Cytotoxics: ifosfamide, chlorambucil, melphalan, busulphan,        cytotoxic antibodies, doxorubicin, epirubicin, plicamycin,        bleomycin, methotrexate, cytarabine, fludarabine, gencitabine,        fluorouracil, mercaptopurine, thioguanine, vincristine,        vinblastine, vindesine, etoposide.    -   Decongestants: pseudoephedrine hydrochloride.    -   Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide,        chlorothiazide, chlorthalidone, ethacrynic acid, frusemide,        metolazone, spironolactone, triamterene.    -   Enzymes: pancreatin, pepsin, lipase.    -   Epilepsy: Gabapentin    -   Anti-parkinsonian agents: bromocriptine mesylate, lysuride        maleate, selegiline, para-fluoroselegiline, lazabemide,        rasagiline, 2-BUMP [N-(2-butyl)-N-methylpropargylamine], M-2-PP        [N-methyl-N-(2-pentyl)-propargylamine], MDL-72145        [beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine],        mofegiline, apomorphine, N-propylnoraporphine, cabergoline,        metergoline, naxagolide, pergolide, piribedil, ropinirole,        terguride, quinagolide.    -   Gastro-intestinal agents: bisacodyl, cimetidine, cisapride,        diphenoxylate HCl, domperidone, metoclopramide, famotidine,        loperamide, mesalazine, nizatidine, esomeprazole, metopimazine,        pantoprazole, ondansetron HCl, Granisetron, tropisetron,        dolasetron, ranitidine HCl, sulphasalazine. Lanzoprazole,    -   Histamine Receptor Antagonists: acrivastine, astemizole,        cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate,        flunarizine HCl, loratadine, meclozine HCl, oxatomide,        terfenadine, triprolidine.    -   Hormone replacement therapy: dydrogesterone    -   Hypertension: Enalapril    -   Lactation: Oxytocin, oxytocin agonists    -   Lipid regulating agents: bezafibrate, clofibrate, fenofibrate,        gemfibrozil, probucol.    -   Local anaesthetics: amethocaine, amylocaine, benzocaine,        bucricaine, bupivacaine, butacaine, butanilicaine, butoxycaine,        butyl aminobenzoate, carticaine, chloroprocaine, cinchocaine,        clibucaine, clormecaine, coca, cocaine, cyclomethycaine,        dimethisoquin, diperodon, dyclocaine, ethyl chloride, ethyl        p-piperidinoacetylaminobenzoate, etidocaine, hexylcaine,        isobutamben, ketocaine, lignocaine, mepivacaine, meprylcaine,        myrtecaine, octacaine, oxethazaine, oxybuprocaine,        parethoxycaine, pramoxine, prilocaine, procaine, propranocaine,        propoxycaine, proxymetacaine, ropivacaine, tolycaine, tricaine,        trimecaine, vadocaine.    -   Motion sickness: diphenhydramine    -   Neuro-muscular agents: pyridostigmine.    -   Nitrates and other anti-anginal agents: amyl nitrate, glyceryl        trinitrate, isosorbide dinitrate, isosorbide mononitrate,        pentaerythritol tetranitrate.    -   Nutritional agents: betacarotene, vitamins, such as vitamin A,        vitamin B₂, vitamin D, vitamin E, vitamin K, minerals.    -   Opioid analgesics: codeine, dextropropyoxyphene, diamorphine,        dihydrocodeine, meptazinol, methadone, morphine, nalbuphine,        pentazocine.    -   Oral vaccines: to prevent or reduce the symptoms of diseases        such as Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping        Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes,        Typhoid, HIV, AIDS, Measles, Lyme disease, Traveller's Diarrhea,        Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies,        Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaires        Disease, Toxoplasmosis, Q-Fever, Haemorrhegic Fever, Argentina        Haemorrhegic Fever, Caries, Chagas Disease, Urinary Tract        Infection caused by E. coli, Pneumococcal Disease, Mumps,        Chikungunya, Hayfever, Asthma, Rheumatoid Arthritis, Carcinomas,        Coccidiosis, Newcastle Disease, Enzootic pneumonia, Feline        leukemia, Atrophic rhinitis, Erysipelas, Foot and Mouth disease        and Swine pneumonia, or to prevent or reduce the symptoms of        diseases caused by Vibrio species, Salmonella species,        Bordetella species, Haemophilus species, Toxoplasmosis gondii,        Cytomegalovirus, Chlamydia species, Streptococcal species,        Norwalk Virus, Escherischia coli, Helicobacter pylori,        Rotavirus, Neisseria gonorrhae, Neisseria meningiditis,        Adenovirus, Epstein Barr Virus, Japanese Encephalitis Virus,        Pneumocystis carini, Herpes simplex, Clostridia species,        Respiratory Syncytial Virus, Klebsiella species, Shigella        species, Pseudomonas aeruginosa, Parvovirus, Campylobacter        species, Rickettsia species, Varicella zoster, Yersinia species,        Ross River Virus, J.C. Virus, Rhodococcus equi, Moraxella        catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica.    -   Voiding dysfunctions: Tamsulosine, trospium chloride,        tolterodine , oxybutinin    -   Proteins, peptides and recombinant drugs: recombinant hormones        and iso-hormones, recombinant cytokines, recombinant        plasminogens, TNF receptor fusion protein, monoclonal        antibodies, nucleic acids, antisense oligonucleotides,        oligonucleotides, glycoproteins and adhesion molecules.    -   Veterinary Arthiritis: Tepoxalin    -   Sex hormones and Contraceptives: clomiphene citrate, danazol,        desogestrel, ethinyloestradiol, ethynodiol, ethynodiol        diacetate, levonorgestrel, medroxyprogesterone acetate,        mestranol, methyltestosterone, norethisterone, norethisterone        enanthate, norgestrel, estradiol, conjugated estrogens,        dydrogesterone, progesterone, stanozolol, stilboestrol,        testosterone, tibolone.    -   Schizoprenia; Olanzapine, Nicergoline    -   Sexual dysfunction: Cabergolin, oxytocin, tadalafil, sildenafil,        vardenafil Spermicides: nonoxynol 9.    -   Stimulants: amphetamine, dexamphetamine, dexfenfluramine,        fenfluramine, mazindol, pemoline.

In a specific, non-limiting embodiment, the active ingredient isdesmopressin acetate. In this embodiment the dosage form can be used invoiding postponement or in the treatment or prevention of incontinence,primary nocturnal enuresis (PNE), nocturia or central diabetesinsipidus. In one embodiment, the amount of desmopressin acetate in thecomposition comprises 0.01-2.00% w/w. In another embodiment, the amountof desmopressin acetate in the composition comprises 0.04-1.00% w/w.

In a specific, non-limiting embodiment, the active ingredient isloratidine. In this embodiment the dosage form can be used e.g. for therelief of nasal or non-nasal symptoms of allergic rhinitis and chronicidiopathic urticaria. In one embodiment, the amount of loratidine in thecomposition comprises 20-40% w/w. In another embodiment, the amount ofloratidine in the composition comprises about 25-40% w/w.

In a specific, non-limiting embodiment, the active ingredient isfamotidine. In this embodiment the dosage form can be used e.g. in thetreatment of gastroesophageal reflux disease, duodenal and gastriculcer, pathological hypersecretory conditions (e.g. Zollinger-Ellisonsyndrome and multiple endocrine adenomas). In one embodiment, the amountof famotidine in the composition comprises 50-90% w/w. In anotherembodiment, the amount of famotidine in the composition comprises 60-90%w/w.

In a specific, non-limiting embodiment, the active ingredient ismontelukast sodium. In this embodiment the dosage form can be used e.g.in prophylaxis and chronic treatment of asthma, allergic rhinitis andexercise-induced bronchoconstriction. In one embodiment, the amount ofmontelukast sodium in the composition comprises 5-40% w/w. In anotherembodiment, the amount of montelukast sodium in the compositioncomprises 5-30% w/w.

In a specific, non-limiting embodiment, the active ingredient isondansetron. In this embodiment the dosage form can be used e.g. in theprevention of postoperative nausea and/or vomiting and also in theprevention of nausea and/or associated with cancer chemotherapy andradiotherapy. In one embodiment, the amount of ondansetron in thecomposition comprises 10-30% w/w. In another embodiment, the amount ofondansetron in the composition comprises about 20% w/w.

A pharmaceutical dosage form of the invention disintegrates, therebyreleasing the active ingredient, upon contact with a fluid (an aqueousmedium or saliva).

Typically, a pharmaceutical dosage form of the invention is anorodispersible pharmaceutical dosage form which disintegrates in themouth within 30 seconds, typically 10 seconds or less.

The term “orodispersible” as used herein should be understood toencompass a solid dosage form which disintegrates or dissolves in themouth within (at most) seconds. In further embodiments, theorodispersible dosage form disperses in the mouth within 10, 9, 8, 7, 6,5, 4, 3, 2, or even within 1 second.

A suitable route of administration for the dosage form of the subjectinvention is oral administration including, but not limited to, buccaland sublingual administration. In a specific embodiment, the dosage formis administered sublingually. Dosage forms of the invention may also beplaced on the tongue or against the cheek or gingiva.

Pharmaceutical dosage forms of the present invention are adapted tosupply the active ingredient to e.g. the oral cavity. The active may beabsorbed across the mucosa at the site of administration, e.g.sublingual mucosa, and/or otherwise, in the case of oral administration,from the oral cavity (e.g. across the buccal and/or gingival mucosa)and/or from the gastrointestinal tract for systemic distribution.

The exact dose and regimen of administration of the dosage form willnecessarily be dependent upon the therapeutic effect to be achieved andmay vary with the particular active ingredient, the route ofadministration, and the age and condition of the individual subject towhom the medicament is to be administered. At times patients may beinstructed to take two or any other number of unit dosage forms in asingle administration or at times only a portion, such as half or aquarter of the unit dosage form in a single administration.

The dosage form of the invention achieves a balance of performance:tensile strength, stability and fast disintegration. It may be producedby known lyophilisate technology. It can be stored (and packed) inblisters but due to its tensile strength, can also be stored and/orpackaged in bottles or bulk. The invention achieves these results in asingle processing step, without the need to resort to multiple stepsincluding granulation.

In addition to the ingredients previously discussed, the matrix may alsoinclude other excipients (auxiliary agents, accessory agents) such as,but not limited to fillers, matrix-forming agents, thickeners (includingbut not limited to guar gum and xanthum gum), binders, diluents,lubricants, pH adjusting agents, protecting agents, viscosity enhancers,wicking agents, non-effervescent disintegrants, effervescentdisintegrants, surfactants, anti-oxidants, wetting agents, colorants,flavouring agents, taste-masking agents, sweeteners, preservatives andso forth.

In one embodiment, a composition of the invention is obtainable bysubliming solvent from a liquid preparation comprising an activeingredient, levan, inulin, and optionally secondary matrix formingagent(s) in a solvent. Typically, the liquid preparation is placed in amould, e.g. such that following sublimination a solid composition,typically in a dosage unit, is formed within the mould. The mould can bean open blister pack whereby the solid dosage unit is formed within theblister pack's depression which is thereafter sealed by a sealing filmor foil.

In one embodiment, the process comprises introducing unit dosagequantities of said preparation into depressions of an open blister pack;and then subliming the preparation to obtain solid dosage forms withinsaid depressions.

The sublimation can be carried out by freeze drying the preparationcomprising the active ingredient, levan, inulin and optionally secondarymatrix forming agent(s) in a solvent. In one embodiment, the solvent iswater.

The invention thus discloses a process for preparing fast-dispersingdosage forms by lyophilizing a combination of an active ingredient,levan, inulin and optionally secondary matrix forming agent(s). Thefast-dispersing dosage form contains a network of the active ingredientand the carriers levan and inulin and optionally the secondary matrixforming agent(s), the network having been obtained by subliming solventfrom the liquid preparation that contains the active ingredient, levan,inulin and the other optional matrix forming agents. Said preparationmay be a solution, suspension or dispersion.

Typically, an initial preparation comprising an active ingredient,levan, inulin and optionally secondary matrix forming agent(s) in asolvent is prepared, followed by sublimation. The sublimation can becarried out by freeze drying the preparation.

In a freeze drying procedure, the preparation (in liquid form) thatcomprises an active ingredient, levan, inulin and any other optionalmatrix forming agent in a solvent is filled into moulds. Each mouldtypically contains a defined amount of such solution with a definedamount of active ingredient. The preparation in the mould is thenfrozen, for example by passing gaseous cooling medium over the mould.After the preparation has been frozen, the solvent is sublimedtherefrom. The sublimation is carried out in a freeze dryer. Inconsequence an open matrix network of levan and inulin optionallytogether with other matrix forming agents included in the solution,carrying the active ingredient, is thereby formed.

The preparation is contained in a mould during the freeze-drying processto produce a solid form in any desired shape. Prior to thelyophilization, the mould may be cooled and frozen (e.g. in afast-freeze tunnel or on the shelves of the lyophilizer), for exampleusing liquid nitrogen or solid carbon dioxide. In one embodiment, thefreezing rate is from 0.1 to 2° C./minute. In another embodiment, thefreezing rate is from 0.5 to 1.5° C./minute. In yet another embodiment,the freezing rate is from 10 to 260° C./minute. In another embodiment,the freezing rate is from 10 to 200° C./minute. In a further embodiment,the freezing rate is from 10 to 160° C./minute.

After lyophilization, the freeze dried compositions can either beremoved from the mould if desired or stored therein until later use.Typically, each mould is so designed so to produce a unit dosage form ofthe composition. The composition so obtained is fast-dispersing anddisintegrates within at most 30 seconds upon contact with fluid,typically within less than 10 seconds.

The solvent is typically water but may optionally also contain aco-solvent (such as an alcohol e.g. tert-butyl alcohol) to improve thesolubility of the chemical.

The composition may contain a pH adjusting agent to adjust the pH of asolution from which the dosage form is prepared within the range of from2 to 10, typically from 3.5 to 9.5 or from 4.5 to 8. Citric acid, sodiumhydroxide, and sodium carbonate can be used as pH adjusting agent, butothers including hydrochloric acid and malic acid can also be used.Non-volatile pH adjusting agents will not be removed by freeze drying orother sublimation processes and so may be present in the final product.

The mould may comprise a series of cylindrical or other shapedepressions in it, each of a size corresponding to a desired size of adosage form to be formed.

In one embodiment, the mould is a depression in a sheet of filmicmaterial. The filmic material may contain more than one depression. Thefilmic material may be similar to that employed in conventional blisterpacks which are used for packaging oral contraceptive tablets and likemedicament forms. For example the filmic material may be made ofthermoplastic material with the depressions formed by thermoforming orcoldforming Polyvinyl chloride film can be used as filmic material.Laminates of filmic material may also be used.

EXAMPLES

The invention is further described in the following examples, which arenot in any way intended to limit the scope of the inventions as claimed.

A. Materials Used in the Examples Presented Below

Material Obtained from Levan (Zymomonas spp.) RealBiotech, Korea Levan(Bacilus spp.) Montana Polysaccharides, USA Citric acid Merck, IndiaMannitol Merck, India Desmopressin acetate Manufactured by PolypeptideLabs A/S, and supplied by Ferring Inulin (from chicory root) BeneoOrafti, Belgium Montelukast Sodium MSN Pharma Chem Pvt. Ltd., India

B. Method for Preparing Placebo Formulation

-   -   1) Dissolve Levan, Inulin and other excipients, if present, in        purified water under stirring at 200 to 500 revolutions per        minute (rpm).    -   2) Optionally adjust the pH of the solution using citric acid        solution or NaOH.    -   3) Make up the final volume of the solution using purified        water.    -   4) Mix the solution under stirring at 200 to 500 rpm for 15        minutes.    -   5) Dose the solution into each cavity of preformed blister        sheets (typically using dispensing pipette).    -   6) Freeze the filled blisters at a temperature in the range of        −20 to −110° C.    -   7) Freeze dry the blisters in a lyophilizer    -   8) Place the blister sheet containing dried lyophilisates on the        punched carrier web of a blister packaging machine to transport        the blister sheets through the sealing station of the packaging        machine.    -   9) Seal the blisters with a lidding foil and punch into final        blisters.

C1. Formulations

The following formulations were prepared using the method described inthe method section “B” above, by freezing the blisters at the rate of0.1-2° C./minute in step 6.

Example—1

Component Amount/unit % w/w Levan (Zymomonas spp.) 18.75 mg 75 Inulin6.25 mg 25 Purified water q.s to 250 μl —

Example—2

Component Amount/unit % w/w Levan (Zymomonas spp.) 16.25 mg 65 Inulin8.75 mg 35 Purified water q.s to 250 μl —

Example—3

Component Amount/unit % w/w Levan (Zymomonas spp.) 12.5 mg 50 Inulin12.5 mg 50 Purified water q.s to 250 μl —

Example—4

Component Amount/unit % w/w Levan (Zymomonas spp.) 8.75 mg 35 Inulin16.25 mg 65 Purified water q.s to 250 μl —

Example—5

Component Amount/unit % w/w Levan (Zymomonas spp.) 6.25 mg 25 Inulin18.75 mg 75 Purified water q.s to 250 μl —

C2. Formulations

The following formulations were prepared using the method described in“B” herein above, by freezing the blisters at a rate of 20-160°C./minute in 4 minutes in step 6.

Example—6

Component Amount/unit % w/w Levan (Zymomonas spp.) 18.75 mg 75 Inulin6.25 mg 25 Purified water q.s to 250 μl —

Example—7

Component Amount/unit % w/w Levan (Zymomonas spp.) 16.25 mg 65 Inulin8.75 mg 35 Purified water q.s to 250 μl —

Example—8

Component Amount/unit % w/w Levan (Zymomonas spp.) 12.5 mg 50 Inulin12.5 mg 50 Purified water q.s to 250 μl —

Example—9

Component Amount/unit % w/w Levan (Zymomonas spp.) 8.75 mg 35 Inulin16.25 mg 65 Purified water q.s to 250 μl —

Example—10

Component Amount/unit % w/w Levan (Zymomonas spp.) 6.25 mg 25 Inulin18.75 mg 75 Purified water q.s to 250 μl —

Example—11

Component Amount/unit % w/w Levan (Zymomonas spp.) 19.5 mg 65 Inulin 3.0mg 10 Mannitol 7.5 mg 25 Purified water q.s to 250 μl —

Example—12

Component Amount/unit % w/w Levan (Zymomonas spp.) 19.5 mg 65 Inulin 6.0mg 20 Mannitol 4.5 mg 15 Purified water q.s to 250 μl —

D. Method for Preparing Dosage Forms Containing Desmopressin

-   -   1) Dissolve Levan, Inulin and other excipients, if present, in        purified water under stirring at 200 to 500 rpm;    -   2) Dissolve Desmopressin acetate in purified water and add to        the solution prepared in step 1.    -   3) Adjust the pH of the solution.    -   4) Make up the final volume of the solution using purified        water.    -   5) Mix the solution under stirring at 200 to 500 rpm for further        5-15 min.    -   6) Dose the solution into cavities of preformed blister sheets        (typically using dispensing pipette).    -   7) Freeze the filled blisters at a temperature in the range of        −20 to −110° C.    -   8) Freeze dry the blisters in a lyophilizer    -   9) Place the blister sheet containing dried lyophilisates on the        punched carrier web of the blister packaging machine, to        transport the blister sheets through the sealing station of the        packaging machine.    -   10) Seal the blister with a lidding foil and punch into final        blisters.

E. Desmopressin Formulations

The following desmopressin lyophilisate formulations were prepared usingthe method described in “D” above, by freezing the blisters at the rateof 0.1-2° C./minute or 20-160° C./minute in step 7.

Example—13

Component Amount/unit % w/w Desmopressin acetate 240 μg 0.95 equivalentto Desmopressin Levan (Zymomonas spp.) 18.75 mg 74.28 Inulin 6.25 mg24.76 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5 Purified waterq.s to 250 μl —

Example—14

Component Amount/unit % w/w Desmopressin acetate 240 μg 0.95 equivalentto Desmopressin Levan (Zymomonas spp.) 16.25 mg 64.38 Inulin 8.75 mg34.66 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5 Purified waterq.s to 250 μl —

Example—15

Component Amount/unit % w/w Desmopressin acetate 240 μg 0.95 equivalentto Desmopressin Levan (Zymomonas spp.) 12.5 mg 49.52 Inulin 12.5 mg49.52 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5 Purified waterq.s to 250 μl —

Example—16

Component Amount/unit % w/w Desmopressin acetate 240 μg 0.95 equivalentto Desmopressin Levan (Zymomonas spp.) 8.75 mg 34.66 Inulin 16.25 mg64.38 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5 Purified waterq.s to 250 μl —

Example—17

Component Amount/unit % w/w Desmopressin acetate 240 μg 0.95 equivalentto Desmopressin Levan (Zymomonas spp.) 6.25 mg 24.76 Inulin 18.75 mg74.28 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5 Purified waterq.s to 250 μl —

F. Method for Preparing Dosage Forms Containing Montelukast Sodium

-   -   1) Dissolve Montelukast in purified water under stirring.    -   2) Dissolve Levan, Inulin and other excipients in the        Montelukast solution of step 1 under stirring at 200-500 rpm.    -   3) Make up the final volume of the solution using purified        water.    -   4) Mix the solution under stirring at 200 to 500 rpm for further        15 min.    -   5) Dose the solution into each cavity of preformed blister.    -   6) Freeze the filled blisters at a temperature in the range of        −20 to −110° C.    -   7) Freeze dry the blisters in a lyophilizer    -   8) Place the blister sheet containing dried lyophilisates on the        punched carrier web of the blister packaging machine, to        transport the blister sheets through the sealing station of the        packaging machine.    -   9) Seal the blister with a lidding foil and punch into final        blisters. 20

G. Montelukast Sodium Formulations

The following Montelukast orodispersible dosage forms were preparedusing the method described in “F” above, by freezing the blisters at therate of 0.1-2° C./minute or 20-160° C./minute in step 6.

Example—18

Component Amount/unit % w/w Montelukast Sodium 4.00 mg 13.79 equivalentto Montelukast Levan 18.75 mg 64.65 Inulin 6.25 mg 21.55 Purified waterq.s to 250 μl —

Example—19

Component Amount/unit % w/w Montelukast Sodium 4.00 mg 13.13 equivalentto Montelukast Levan 18.75 mg 61.57 Inulin 6.25 mg 20.52 Mannitol 1.45mg 4.77 Purified water q.s to 250 μl —

H. Comparative Examples Example—20

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but using pullulan in place ofcombination of levan and inulin, and freezing the blisters at the rateof 20-260° C./minute in 4 minutes in step 6.

Component Amount/unit % w/w Pullulan 25 mg 100 Purified water q.s 250 μl—

Example—21

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking HPMC in place of combinationof levan and inulin, and freezing the blisters at the rate of 0.1-2°C./minute in step 6.

Component Amount/unit % w/w HPMC 25 mg 100 Purified water q.s 250 μl —

Example—22

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking HPMC in place of combinationof levan and inulin, and freezing the blisters at the rate of 20-160°C./minute in ≦4 minutes in step 6.

Component Amount/unit % w/w HPMC 25 mg 100 Purified water q.s 250 μl —

Example—23

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking methyl cellulose in place ofcombination of levan and inulin, and freezing the blisters at the rateof 0.1-2° C./minute in step 6.

Component Amount/unit % w/w Methyl cellulose 25 mg 100 Purified waterq.s 250 μl —

Example—24

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking methyl cellulose in place ofcombination of levan and inulin, and freezing the blisters at the rateof 20-160° C./minute in 4 minutes in step 6.

Component Amount/unit % w/w Methyl cellulose 25 mg 100 Purified waterq.s 250 μl —

Example—25

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking gum tragacanth in place ofcombination of levan and inulin, and freezing the blisters at the rateof 0.1-2° C./minute in step 6.

Component Amount/unit % w/w Gum tragacanth 25 mg 100 Purified water q.s250 μl —

Example—26

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking gum tragacanth in place ofcombination of levan and inulin, and freezing the blisters at the rateof 20-160° C./minute in 4 minutes in step 6.

Component Amount/unit % w/w Gum tragacanth 25 mg 100 Purified water q.s250 μl —

Example—27

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking Fish gelatin in place ofcombination of levan and inulin, and freezing the blisters at the rateof 0.1-2° C./minute in step 6.

Component Amount/unit % w/w Fish gelatin 25 mg 100 Purified water q.s250 μl —

The lyophilisates obtained were very fragile and were broken intosmaller pieces. No further analysis could be carried out.

Example—28

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking Fish gelatin in place ofcombination of levan and inulin, and freezing the blisters at the rateof 20-160° C./minute in 4 minutes in step 6.

Component Amount/unit % w/w Fish gelatin 25 mg 100 Purified water q.s250 μl —

Example—29

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking Fish gelatin in place ofcombination of levan and inulin, and freezing the blisters at the rateof 0.1-2° C./minute in step 6.

Component Amount/unit % w/w Fish gelatin 12.5 mg 50 Mannitol 12.5 mg 50Purified water q.s 250 μl —

Example—30

Comparative lyophilisates were prepared according to the methoddescribed in “B” herein above, but taking fish gelatin in place ofcombination of levan and inulin, and freezing the blisters at the rateof 20-160° C./minute in ≦4 minutes in step 6.

Component Amount/unit % w/w Fish gelatin 12.5 mg 50 Mannitol 12.5 mg 50Purified water q.s 250 μl —

I. Disintegration Tests Ia. Disintegration Test in Petri Dish

This test measures the expected disintegration time of a composition ofthe invention in an aqueous medium which is an indication of itsdisintegration time in saliva.

The disintegration rate of all the lyophilisates on a wet filter paperwas determined according to the method described in PCT applicationWO2009002084, page 12 paragraph 129, wherein the test was performed at atemperature of about 25±2° C.

Ib. Measurement of Oral Dissolving Time (ODT) of Placebos

The dissolving time of the placebo lyophilisates in the oral cavity wasdetermined according to the method described in PCT applicationWO2009002084, page 12 paragraph 132, wherein the lyophilisate was placedon the tongue of a healthy human adult and then measuring the time forit to completely dissolve while rubbing the lyophilisates between thetongue and the upper palate. The mean ODT was calculated from the dataobtained from 5 healthy human adults.

J. Method for Testing Disintegration Time (Invitro DT)

This test measures the disintegration time of the compositions of theinvention in aqueous medium which is an indication of theirdisintegration time in saliva.

Equipment: Electrolab, Model: ED2 SAPO

Procedure: The method was followed as per USP 31-NF 26 (GeneralChapters, <701>Disintegration) and Ph Eur. 1997 (2.9.1. Disintegrationof tablets and capsules). Water was filled into the beaker andmaintained at 37° C.±0.5° C. using water bath. The lyophilisates wereplaced in sinker made up of copper wire or stainless steel with diameterof about 0.5 mm (±0.05 mm) and length of about 15 mm. The lyophilisateswere then placed into the basket of basket rack assembly and instrumentwas set on. The disintegration time was noted in seconds.

K. Method for Testing Tensile Strength

Equipment: Engineering Systems (NOTTM) Ltd, Model: 5 kN Testing Machine

Procedure: The method for determining tensile strength was fed into theinstrument. The parameters test speed (15 mm/min), fracture mode, unit(Newton, [N]), fracture percentage (80%), low limit (0.1), and distancebetween the supporting edges (4.5-6 mm) were set into the instrument. Aload cell of 10 kg was used and the tensile strength was calculatedusing the following formula:

${N\text{/}{{mm}2}} = \frac{3 \times {Mean}\mspace{14mu} (N) \times {Distance}\mspace{14mu} {between}\mspace{14mu} {two}{\mspace{11mu} \;}{supporting}\mspace{14mu} {axis}\mspace{14mu} {in}\mspace{14mu} {mm}}{2 \times \left( {{Thickness}\mspace{14mu} {in}\mspace{14mu} {mm}} \right)^{2} \times \left( {{Diameter}\mspace{14mu} {in}\mspace{14mu} {mm}} \right)}$

Thickness and diameter were determined using vernier calliper.

Tensile strength of commercially available Nimulid-MD, an orodispersibletablet of Nimesulide prepared by conventional compression technique wasfound to be 1.14 N/mm²

L. Dissolution Method

This test measures the dissolution (%) of an active ingredient from acomposition of the invention in aqueous medium which is an indication ofthe release rate of the active ingredient from the composition.

Procedure: The dissolution time of the lyophilisates containing anactive ingredient was measured as follows: The method was followed asper USP 32-NF 27 (General Chapters, <711>Dissolution). Dissolution media(0.1N HCl, Phosphate buffer pH 6.8, Acetate buffer pH 4.5, or 0.5% SLSin water) was selected on the basis of the active ingredient in thecomposition. Dissolution bowls were filled with appropriate media volume(500 mL or 900 mL) on the basis of the active ingredient in thecomposition and the temperature of the media was maintained at 37°C.±0.5° C. using water bath. The apparatus used was USP type II (Paddle)and set at the required rpm (50 rpm) as per the test procedure. Sampleswere withdrawn as per the time point (5 min, 10 min, 15 min, and 30 min)defined in the test procedure. Samples were analyzed chromatographicallyor by UV as per the test procedure and % release was calculated.

The disintegration rates, ODT, in-vitro DT, tensile strength andDissolution data for the lyophilisates prepared according to examples 1to 19, and comparative examples 20 to 30 are presented in table 1.

TABLE 1 Disintegration Oral In-vitro Tensile Dissolution Example test inpetri dissolving DT strength (5/15 minutes) No dish (sec) time (sec)(sec) (N/mm²) (%) 1 3 5 2 1.19 NA 2 5 5 2 1.04 NA 3 2 4 2 1.21 NA 4 2 32 0.60 NA 5 2 3 2 0.59 NA 6 3 3 2 0.19 NA 7 2 4 2 0.20 NA 8 2 3 2 0.19NA 9 3 2 2 0.10 NA 10 3 2 2 0.08 NA 11 6 4 3 0.14 NA 12 1 4 3 0.18 NA 132 NA 2 1.13  95/100 14 2 NA 2 1.13 100/101 15 3 NA 2 0.87  99/102 16 3NA 2 0.50 104/105 17 2 NA 2 0.37 101/104 18 2 NA 1 0.13 99/99 19 2 NA 10.19  99/101 20 32 30 196 0.80 NA 21 150 39 124 0.97 NA 22 35 51 1280.27 NA 23 >300 190 >30 minutes <0.05 NA 24 >300 192 >30 minutes <0.05NA 25 25 22 40 <0.05 NA 26 36 30 20 <0.05 NA 28 2 5 <2 <0.05 NA 29 2 3<2 0.15 NA 30 2 4 <2 0.06 NA NA—Not Applicable for column 3 as the oraldissolving time was measured for placebo lyophilisates only. NA—Notapplicable for column 6 as the dissolution time was measured forlyophilisate containing drug substances only.

1. A pharmaceutical composition comprising an open matrix networkcarrying a pharmaceutically active ingredient, wherein the open matrixnetwork comprises levan and inulin.
 2. A pharmaceutical compositioncomprising a matrix carrying a pharmaceutically active ingredient, thematrix rapidly disintegrating upon contact with an aqueous medium orwith saliva, said matrix comprising levan and inulin.
 3. Apharmaceutical composition according to claim 1, wherein the matrixfurther comprises mannitol.
 4. A pharmaceutical composition according toclaim 1, wherein the matrix further comprises trehalose.
 5. Apharmaceutical composition according to claim 1, wherein the matrixfurther comprises raffinose.
 6. A pharmaceutical composition accordingto claim 1, wherein at least 80% of the composition is dissolved in anaqueous medium or saliva within 30 seconds.
 7. A pharmaceuticalcomposition according to claim 6, wherein at least 80% of thecomposition is dissolved in an aqueous medium or saliva within 10seconds.
 8. A pharmaceutical composition according to claim 1 having atensile strength of about 0.05-1.6 N/mm² and a rapid dissolution ratesuch that at least 80% of the composition is dissolved in an aqueousmedium or saliva within 30 seconds.
 9. A pharmaceutical compositionaccording to claim 8 wherein the composition is dissolved in an aqueousmedium or saliva within 10 seconds.
 10. A pharmaceutical compositionaccording to claim 1, in an oral dosage form.
 11. A pharmaceuticalcomposition according to claim 10 which is adapted for sublingualadministration.
 12. A pharmaceutical composition according to claim 1,obtainable by subliming a solvent from a liquid preparation comprisingthe active ingredient and levan and inulin in a solvent.
 13. Apharmaceutical composition according to claim 12, wherein thesublimation is carried out by freeze drying the preparation.
 14. Apharmaceutical composition according to claim 1, wherein the activeingredient is desmopressin acetate.
 15. A pharmaceutical compositionaccording to claim 1, wherein the active ingredient is loratidine.
 16. Apharmaceutical composition according to claim 1, wherein the activeingredient is famotidine.
 17. A pharmaceutical composition according toclaim 1, wherein the active ingredient is montelukast sodium.
 18. Apharmaceutical composition according to claim 1, wherein the activeingredient is ondansetron.
 19. A process for preparing a pharmaceuticalcomposition comprising subliming a solvent from a liquid preparationcomprising a pharmaceutically active ingredient and levan and inulin inthe solvent.
 20. A process according to claim 19, comprising: (a)introducing unit dosage quantities of said liquid preparation intodepressions of an open blister pack; and (b) subliming the preparationto obtain solid unit dosage forms within said depressions.
 21. A processaccording to claim 20, wherein the sublimation is carried out by freezedrying the preparation.
 22. A process according to claim 21, wherein thesolvent is water.
 23. A process according to claim 19, wherein theactive ingredient is desmopressin.
 24. A process according to claim 19,wherein the active ingredient is loratidine.
 25. A process according toclaim 19, wherein the active ingredient is famotidine.
 26. A processaccording to claim 19, wherein the active ingredient is montelukastsodium.
 27. A process according to claim 19, wherein the activeingredient is ondansetron.
 28. A process for the preparation of apharmaceutical composition comprising: (a) preparing a solutioncomprising levan, inulin and an active ingredient in a solvent; (b)freezing said solution; (c) subliming the solvent from the frozensolution, wherein the pharmaceutical composition so obtaineddisintegrates within 30 seconds upon contact with an aqueous solution orsaliva.
 29. A process according to claim 28, wherein the pharmaceuticalcomposition obtained disintegrates within 10 seconds upon contact withan aqueous solution or saliva.
 30. (canceled)